Fifty shades of Troponin - Dr Liam Penny
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Fifty shades of Troponin
Dr Liam Penny
The Queens Hotel, Cheltenham
4th October 2012
Plaque-fissure and intracoronary thrombus
Courtesy Prof. MJ Davies
Acute Coronary Syndromes
Plaque-fissure and intracoronary thrombus
Plaque
Rupture
Old term Stable Unstable Non– Q-wave
Angina Angina Q-wave MI MI
CPK normal Enymes raised (CPK)
Acute Coronary Syndromes
Plaque-fissure and intracoronary thrombus
Plaque
Rupture
Old term Stable Unstable Non– Q-wave
Angina Angina Q-wave MI MI
New term Stable Angina ACS NSTEMI STEMI
Tn - Tn + Tn + Tn ++
Coronary Embolism in patient dying with ACS
Acute Coronary Syndromes
Why Troponin ?
Main value is for Risk stratification
Any rise in Troponin Predicts Risk of complications in ACS
Increasing Troponin Predicts increasing Risk
Wright, R. S. et al. J Am Coll Cardiol 2011;57:e215-e367
Troponin predicts which ACS patients benefit from Invasive strategy
1021 patients 7 yr follow up study
Comparison of Kaplan–Meier Survival for the 2 ACS groups and with the reference
population.
Wong P S C et al. Postgrad Med J 2012;88:437-442Comparison of Kaplan–Meier Survival for the two non ACS groups and with the reference population.
Comparison of Kaplan–Meier Survival for the four
troponin groups
Tn + , non ACS had worst prognosis.
Wong P S C et al. Postgrad Med J 2012;88:437-442Definition of AMI
WHO definition of AMI 1971
• CPK raised > 2 normal
– arbitrary level
– assay was unreliable with wide inter-individual
and intra-individual variations
– many other causes of raised CPKESC/ AHA 2000 definition of AMI NB Any rise or fall of Tn
New clinical classification of MI
Classification Description
1 Spontaneous MI related to ischemia due to a primary coronary
event, such as plaque erosion and/or rupture, fissuring, or
dissection
2 MI secondary to ischemia due to an imbalance of O2 supply and
demand, as from coronary spasm or embolism, anemia,
arrhythmias, hypertension, or hypotension
3 Sudden unexpected cardiac death
4a MI associated with PCI
4b MI associated with documented in-stent thrombosis
5 MI associated with CABG surgery
Thygesen K et al. Circulation 2007;ESC/ ACC definition of AMI • Based on more sensitive and more specific Tn assays but ….
Problems with ESC /ACC definition
• Wide variation in early Tn assays at low levels
– Eg same patient assayed in 2 different laboratories
one will determine AMI other will notProblems with ESC /ACC definition • Tn raised in other conditions apart from ACS – 68% of marathon runners Ann Emerg Med. 2007;49:137-143 – 19.6% of angioplasties but normal CKMB J Am Coll Cardiol 2006;48:1765–70 – Treadmill exercise test ie reversible ischemia not necessarily necrosis – ‘Healthy’ population
RAISED TROPONINS ON A STROKE UNIT:
412 patients with Stroke
70 (29%) patients had positive Tn levels
(>0.032 ng/l)
NB Must view clinical context to interprete rise in Tn
doi:10.1136/heartjnl-2011-300198.4BCS Working Group
Definition of Myocardial Infarction
Heart 2004BCS Working Group proposals
1. ACS with unstable angina Tn –
2. ACS with myocyte necrosis Tn +
transient ECG changes
3. ACS with clinical MI
evolving ECG changes
– Tn I >1.0ng/ml or Tn T >0.5ng/ml
• Roughly corresponds with 1971 WHO definition CPK x2
Arbitrary cut-off2007 Thygesen K et al. Circulation. 2007 Nov 27;116(22):2634-53
Circulation 2012
Electrocardiogram (ECG)
ECG Evolution in ST Elevation
Myocardial Infarction
30ECG can also be non-specific for diagnosing MI
Diagnostic criteria for AMI • Evidence of myocardial necrosis (rise in Tn) in the clinical setting consistent with AMI • At least 1 of the following – Symptoms of Ischaemia – New ST T or LBBB or Q waves – Imaging evidence of new WMA – *Coronary Thrombus at angio or PM Special situations eg Sudden death, PCI/CABG related MI
Wide variation between laboratories in Tn I assay
Troponin level (mcg/L) depends on assay
The diagnostic cut-offs used in new definition (99 centile) th
are one order of magnitude lower than those proposed by BCS
Method 99th centile Original AMI cut off
mcg/l mcg/l
Abbott AxSym Trop I 0.4 (95th centile) 2.0
Abbott ARCHITECT Trop I 0.012 0.3
ADVIA Centaur cTnI 0.07 (95th centile) 1.5
ADVIA Centaur TnI-Ultra 0.04 0.78
Access Accu TnI 0.04 0.5
Dade Behring Dimension Trop I 0.07 0.6
Dade Behring Stratus Trop I 0.07 0.6
IMMULITE 2500 Trop I 0.2 0.9
Ortho VITROS cTnI 0.08 0.4
Ortho VITROS TropI 0.12
Tosoh AIA Trop I 0.1 0.1
Roche Elecsys Troponin TElevation of TN • > 99 upper percentile • COV 5%
Impact of Cardiac Troponins
298 Patients with Chest Pain Admitted to CCU
155 (52%) 127 (43%) 16 (5%)
MI by WHO criteria Ischemia Non-Cardiac
100% positive cTnT 44 patients 83 patients
Troponin T
positive cTnT negative cTnT
positive
defined as >
(15%) 6/44 (14%) 3/83 (4%) 0.2
Death or Mi Death or MI Death or MI micrograms/L
in 6 months in 6 months in 6 months
Ravkilde J, et al Scand J Clin Lab Invest 1993 Nov;53(7):677-85Impact of Cardiac Troponins
298 Patients with Chest Pain Admitted to CCU
155 (52%) 127 (43%) 16 (5%)
MI by WHO criteria Ischemia Non-Cardiac
100% positive cTnT 44 patients 83 patients
positive cTnT negative cTnT Troponin T
positive
defined as >
(15%) 6/44 (14%) 3/83 (4%) 0.2
Death or Mi Death or MI Death or MI micrograms/L
in 6 months in 6 months in 6 months
Ravkilde J et al, Scand J Clin Lab Invest 1993 Nov;53(7):677-85 37Acute Coronary Syndromes
What about high sensitivity
Troponin ?Raised hs TN • 2% “healthy” adults • Stable Angina • Pulmonary Hypertension • LVH • Heart Failure • Renal Failure
Diagnosis of AMI with hsTn • Requires 2 samples • Show 20% to 50% rise after 3 hrs
High Sensitivity Troponin
Detects levels 10X lower than older assays
1. Greater sensitivity
2. Greater precision than older assays
3. Peaks earlier post MI (3hrs)
4. ?positive in some ‘well’ individuals
Christ M et al, American J Med (2010) 123, 1134-1142
Mohammed AA et al. Cardiology in Review 2010;18: 12–19
41Troponin level (mcg/L) depends on assay
The diagnostic cut-offs used in new definition (99 centile) th
are one order of magnitude lower than those proposed by BCS
Method 99th centile Original AMI cut off
mcg/l mcg/l
Abbott AxSym Trop I 0.4 (95th centile) 2.0
Abbott ARCHITECT Trop I 0.012 0.3
ADVIA Centaur cTnI 0.07 (95th centile) 1.5
ADVIA Centaur TnI-Ultra 0.04 0.78
Access Accu TnI 0.04 0.5
Dade Behring Dimension 0.07 0.6
Trop I
Dade Behring Stratus Trop I 0.07 0.6
IMMULITE 2500 Trop I 0.2 0.9
Ortho VITROS cTnI 0.08 0.4
Ortho VITROS TropI 0.12
Tosoh AIA Trop I 0.1 0.1
Roche Elecsys Troponin Ths Troponin detected in 70% ‘well’ subjects > 65 yrs
Baseline Tn predicted Death over 10 yrs.
deFilippi, C. R. et al. JAMA 2010;304:2494-2502hs Troponin elevated in 70% ‘well’ subjects > 65 yrs
Baseline Tn predicted Death over 10 yrs.
deFilippi, C. R. et al. JAMA 2010;304:2494-2502Subsequent Change in hs Tn predicts
development of Heart Failure and Cardiovascular Death
deFilippi, C. R. et al. JAMA 2010;304:2494-2502Accuracy of Troponin depends on time since pain onset hs Troponin accurate at 2 hrs, standard Tn 12 hrs
Impact of Troponins on MI Incidence
Circulation 2003;108:2543-9
47Impact hsTn vs Tn STEMI diagnosis by 20%
old new
48In Edinburgh introducing hsTn
increased myocardial infarction diagnosis by 33%
Heart 2011Acute Myocardial Infarction Other markers to define AMI?
Role of other Biomarkers to define AMI: Copeptin
Copeptin and Tn Levels in Relation to Time Since Onset of Symptoms
Copeptin is an early marker
Reichlin, T. et al. J Am Coll Cardiol 2009;54:60-68Acute Myocardial Infacrtion
What about adefinition based on
Ejection Fraction?Comparison between Echo and Nuclear EF in same subject
Inter-observer variation Echo mean diff = 18.1% Nuclear mean diff = 3.1%
Other Factors Influencing EF
• Load on LV
– HT reduces EF (Normal = 0.45)
– Optimal treatment (3 months post MI)
• Mitral Regurgitation increases EF
– If MR, even EF < 0.6 is impaired
56Conclusions
•Level of Tn which can now be reliably measured (99th Percentile and 10% CV)
is 1% of original definition recommended by BCS
•Consequently in ACS spectrum less Unstable AP and more MI diagnosed
TN increased MI diagnosis by 33%
hs TN increased MI diagnosis by further 33%
•Hs Tn measured in many ‘normals’ and non ACS patients
•Interpretation relies not on level but on clinical contextCase Study 1
Modern Treatment further complicates
• RP male 55yrs Smoker
2011 Admitted 22.20hrs
Pain onset 20.00 hrs
ECG ST elevation inferior leads
Tn on admissionCase Studies
• RP male 55yrs Smoker
ECG ?small q waves
Echo Normal EF 70%
? Small area inf hypokinesia
Conclusion
Treated in early hrs of ?threatened inferior MICase Study2 Is this a valid claim ?
69 yrs female
While standing off stage just before a Ball Room dancing competition
became distressed with palpitations and a tightness in her chest. She collapsed.
PMH – b/l mastectomy
Non smoker, no FH of note
Meds - Tamoxifen 20mg /Omeprazole 20mg
Examination – unremarkable
IX - ECG
Troponin T – 0.02ECG on admission
ECG at 12 hrs
Diagnosis : Acute Coronary Syndrome Transferred that day to UHW because of ongoing pain and ECG changes despite IV Nitrates and LMW Heparin
Echo cardiogram On presentation UHW
Normal right coronary anatomy
Normal left coronary anatomy
Normal left coronary anatomy
Echo cardiogram On presentation UHW
Echo cardiogram At 1 month
???? Diagnosis
TAKO - TSUBO SYNDROME ‘Transient LV apical ballooning’ ‘Reversible cardiomyopathy’
Tako-tsuba Syndrome: Peculiar LV End systolic shape
Tako-tsubo Syndrome
Incidence
• Probably accounts for >5% ACS
Eur Heart J. 2006 Jul;27(13):1523-9.Left ventricular EF independently predicts prognosis
New Terminology in ACS
Plaque
Rupture
Stable Unstable Non– Q-wave
Old term Angina Angina Q-wave MI MI
Increasing Tn levels
New term Atherothrombosis UA/NSTEMI STEMI
Cannon CP. J Thromb Thrombolysis. 1995;2:205-218.Importance of very small elevations in Tn
Kontos et al68 yrs female collapsed after finding her son in the garage having hanged himself
69 yrs female Christmas Eve shopping her purse was stolen and she became very distressed and collapsed with Chest pain
5 days later
79 yrs female while picking blackcurrants in her garden had a bee sting, became distressed and then about 1 hr later developed chest pain and husband called 999
Histology of Ruptured plaque
Causes of Increased
Troponin
Mohammed AA et al,Cardiology in Review
2010;18: 12–19
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